E3Gen: Multigenerational effects of toxicant exposures on life course health and neurocognitive outcomes in the ELEMENT birth cohorts SUMMARY The impact of environmental toxicants on health and disease risk during sensitive developmental periods has been recognized for nearly 20 years, as highlighted by the developmental origins of adult disease hypothesis and life course epidemiology. Yet, the potential to understand novel mechanisms implicit in these frameworks has not been fully realized. Few environmental cohorts have followed mother-child dyads beyond adolescence, precluding the ability to understand long-term impacts of toxicant exposures in young adulthood and perimenopause?both dynamic life stages characterized by increased risk of metabolic syndrome and potential changes in neurocognitive processes. The E3Gen project, based on our highly successful, 22-year research collaboration with the Instituto Nacional de Salud Pblica de Mexico (INSP), comprises three birth cohorts of women originally recruited from 1994- 2004, their children now aged 12-22 years, and the next generation of grandchildren currently being born. This R24 application leverages the research infrastructure of our ongoing studies in the Early Life Exposure in Mexico to ENvironmental Toxicants (ELEMENT) cohorts and of three NIEHS-funded centers at the University of Michigan, creating an unparalleled opportunity launch new research that maximizes use of the existing biorepository and rich database of repeated toxicant exposures and metabolic and neurocognitive outcomes and that promotes accelerated data and resource sharing with the larger environmental health sciences community. Specific Aims are to: 1) Maintain and enhance the scientific integrity of the E3Gen multigenerational cohort and implement strategies to encourage participation and prevent loss to follow up among 850 mothers aged 38-50 years, their children aged 12-22 years, while also recruiting 90 grandchildren currently and projected to be born over the next five years; 2) Prepare for future scientific studies considering the roles of epigenetics, oral health and oral microbiome in mediating the impact of endocrine disrupting chemicals (EDCs) and metals on metabolic and neurocognitive outcomes across three generations of ELEMENT participants; 3) Develop and test novel data management techniques to improve and enrich data integration and harmonization, data sharing, and cross-project data communication.